5-nitro-furfurylidene antimicrobic agents

ABSTRACT

For combating and preventing infections caused by a variety of microbes such as bacteria and Trichomonas vaginalis, new compounds of the formula WHEREIN X is O, S or NH; Y is O; S; -CH2-O-; -S-CH2-; -CH2-S-; -O-CH2-; -SO-; -SO-CH2-; CH2-SO-; -CH2-SO2-; -SO2-CH2- or -CA2-, A being H, methyl, ethyl or phenyl; and R1, R2 and R3 each represents alkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxyalkoxy, mono- or dialkylaminoalkyl, dialkylaminoalkoxy, amino, acylamino, mono- or dialkylamino, alkylsulfonylamino, acyloxy, alkylsulfonyloxy, benzyloxy groups wherein each alkyl, alkoxy or acyl residue is not more than five carbon atoms and acyl is derived from a carboxylic acid; halogen; or hydrogen with the provision that when Y represents -CH2-, at least one of R1, R2, and R3 is other than hydrogen.

United States Patent [191 Albrecht et a1.

[ 51 Feb. 13, 1973 S-NITRO-FURFURYLIDENE ANTIMICROBIC AGENTS [75]Inventors: Rudolf Albrecht; Eberhard Schroder, both of Berlin, Germany;Mahmoud Muttic, Cornavin- Geneve, Switzerland [73] Assignee: ScheringAG, Berlin and Bergkamen, Germany; by said Albrecht and Schroder [22]Filed: 0ct.3l,l968

[21] Appl. No.: 804,333

[30] Foreign Application Priority Data Nov. 14, 1967 Germany ..Sch 41572[52] US. Cl. ..260/240 A, 260/327 B, 260/330.5, 260/345.2, 260/346.2 R,260/488 CD,

[51] Int. Cl. ..C07d 5/30 [58] Field of Search ..260/240 A [56]References Cited OTHER PUBLICATIONS pp. 589-592 (May 1968). Tirouflet etal., Comptes Rendus, Vol. 250, pp.

1276 to 1278 (1960). Miura et al., Progress in Medicinal Chemistry Vol.5, chapter 6, pages 320-322, 329333, Butterworths, London (1967).

Primary Examiner-Henry R. Jiles Assistant Examiner-G. Thomas ToddAttorneyMillen, Raptes & White 57] ABSTRACT For combating and preventinginfections caused by a variety of microbes such as bacteria andTrichomonas vaginalis, new compounds of the formula with 'SO2CH2 01''CA2- A being H, methyl, ethyl or phenyl; and R R and R each representsalkyl, hydroxy,

hydroxyalk l, alkoxy, alkoxyalk l, alkoxyalkoxy, monoor ialkylammoalkyl,dia kylaminoalkoxy,

amino, acylamino, monoor dialkylamino, alkylsulfonylamino, acyloxy,alkylsulfonyloxy, benzyloxy groups wherein each alkyl, alkoxy or acylresidue is not more than five carbon atoms and acyl is derived from acarboxylic acid; halogen; or hydrogen with the provision that when Yrepresents CH at least one of R R and R is other than hydrogen.

13 Claims, No Drawings S-NITRO-FURFURYLIDENE ANTIMICROBIC AGENTSBACKGROUND OF THE INVENTION This invention relates to compoundsstructurally novel and unobvious but somewhat analogous to 2-(5-nitro-furfurylidene)-indanone.

The latter compound, though known, is not a particularly outstandingagent for the treatment of infections caused by such microorganisms asTrichorrionas vaginalis, M. tuberculosis, M. battey, M. avium, and M.kanasii and others. However, there is a genuine need for drugs whichwould be'effective against such intractable infections.

SUMMARY OF THE INVENTION Relevant to the above need, an object of thisinvention is to provide antimicrobic pharmaceutical compositions andmethods of administration especially applicable to the precedingmicrobes.

Another object of this invention is to provide novel chemical compounds,as well as processes and intermediates for their manufacture.

Upon further study of the specification and claims, other objects andadvantages of the present invention will become apparent.

To attain the above objects there are provided compounds of thefollowing Formula I:

O I OzN on x wherein X is O, S or NH;

A being H, methyl, ethyl or phenyl; and

R,R being identical or different, represent alkyl,

hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, alkoxy-alkoxy, monoordialkylaminoalkyl, dialkylaminoalkoxy, amino, acylamino, monoordialkylamino, alkylsulfonyl-amino, acyloxy, alkylsulfonyloxy, benzyloxygroups, wherein each alkyl, alkoxy or acyl residue is preferably of nomore than five carbon atoms; halogen; or hydrogen, with the provisionthat when Y is CH,-, the residues R, R, cannot all represent hydrogen.Mixtures of these compounds are also effective.

DETAILED DISCUSSION OF THE INVENTION Respecting the definition of R,, Rand R, in the above formula, it is preferred that at least one of samerepresents hydroxy or alkoxy of one to two carbon atoms, such asmethoxy.

It is also preferred that when Y is CH,, at least two R,-R,, are nothydrogen, preferably at least one being alkoxy or hydroxy.

Of particular importance, moreover, are the compounds wherein one ofR,R, is hydroxy and another is alkoxy.

Additional preferred subgeneric groups which are especially unobviousfrom the standpoint of structural chemistry are as follows:

a. X represents S or NH;

5 b. Y is otherothan CH,---;

0. Y is other than CH,- and preferably at least one of R,-R, is otherthan H, particularly other than alkyl;

d. Y is CH, and at least one of R,-R, is hydroxyalkyl, alkoxyalkyl,alkoxyalkoxy, monoor dialkylaminoalkyl, dialkylaminoalkoxy, amino,acylamino, monoor dialkylamino, alkylsulfonylamino, acyloxy,alkylsulfonyloxy, or benzyloxy, wherein the acyl portion is derived froma carboxylic acid.

The novel compounds can be prepared by the following processes:

a. An aldehyde of the general Formula II X has ,the above-indicatedmeanings, or a functional derivative of the aldehyde, is reacted with acompound of the general Formula III c. with the provision that Y in thefinal product SO,,CH or CH,-SO group, a compound of the general FormulaV as follows is subjected to an oxidizing reaction:

U I J i i /It, OzN \x mgu f /l ilpm wherein X and R, R, have theabove-indicated meanings,

and

B represents the groups --S-, SCH,,

CH,-S- or optionally SO, SOCH or CH,--.

The process according to (a) is conducted at room temperature or anelevated temperature in an acidic reaction medium, for example, inglacial acetic acid in the presence of concentrated sulfuric acid, or inorthophosphoric acid. The reaction can also be carried out in an acidanhydride at an elevated temperature. Any esterification of hydroxylgroups, which can occur during this reaction, can be reversed bysaponification. Preferred functional derivatives of the aldehydes arethe diacetates.

The nitration in accordance with (b) can be conducted along the lines ofthe conventional methods, e.g., with nitric acid in HOAc/Ac O.

The oxidation of the sulfur in the compound of general Formula V to thesulfoxide or to the sulfone can be conducted, for example, with hydrogenperoxide. The sulfone can also be obtained by oxidation of thesulfoxide.

The compounds of Formula 1 are crystalline substances and are slightly,if at all, soluble in water. They can be isolated from their synthesisreaction mixtures by the introduction of ice water. For purificationpurposes, the compounds can be recrystallized, for example, fromethanol, ethyl acetate, glacial acetic acid, dioxane, tetrahydrofuran ornitromethane.

The novel compounds exhibit good antimicrobic effects, particularlyagainst Trichomonas vaginalis and M ycobacterium tuberculosis. Table 1shows the superior effectiveness of the novel substances againstTrichomonas vaginalis, using examples of the compound of Formula I incomparison with 2-(5-nitrofurfurylidene)-indanone (VI), the latter beingpreviously disclosed in a published Japanese Patent Application 41/2552.The novel compounds of Formula I are particularly successful for theoral treatment of Trichomonas vaginalis infections. Thus, inpharmacological tests, it has been determined that the curative oraldosage (CD administered to mice once daily, is about 17 mg per kg ofbody weight.

Table II demonstrates the antimicrobic effect of the compounds of thisinvention against Mycobacteria in comparison with compound Vl (platetest). Likewise, in the tube test,2-(5-nitro-2-furfurylidene)-5-acetoxyindanone exhibits a minimuminhibitory concentration of l'y/ml against Mycobacterium tuberculosisand 0.1 y/ml against M ycobacterium avium. The latter compound is alsoeffective in vivo, as can be seen from the following experiment: Groupsof 5 mice each were infected with Mycobacterium tuberculosis H Rvintravenously l mg/mouse). Eleven days after infection, whereas alluntreated animals had died, of those animals treated once with lOO mg/kgsubcutaneously 48 hours before infection, four out of five remainedalive.

Compounds of Formula I exhibit an antimicrobic effect over anextraordinarily broad range, i.e., against gram-positive andgram-negative bacteria, mycobacteria and fungi, so that the compoundscan be employed as antiseptics. The minimum inhibitory concentrations oftypical compounds against a wide variety of microbes are compiled inTable [IL The toxicity of the novel compounds is negligible as in allcases it is greater than 4 g. /kg;=accordingly the therapeutic index ofthe compounds of this invention is very high. The novel compounds areespecially suitable for the treatment of trichomoniasis andtuberculosis.

Because the compounds of this invention can be employed in vitro as wellas invivo, they are especially useful as disinfectants, e.g., in thesterilization of medical instruments and the like, as well as incleansing solutions for cleaning woodwork, towels, linen, blankets,dishes and the like, to prevent spread of infection.

The novel compounds of this invention can be employed in mixture withconventional pharmaceutical excipients. Carrier substances can be suchorganic or inorganic substances suitable for parenteral, enteral, ortopical application, and which, of course, do not deleteriously reactwith the novel compounds, such as, for example, water, vegetable oils,polyethylene glycols, gelatin, lactose, amylose, magnesium stearate,talc, vaseline, cholesterol, etc.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions, as well as suspensions, emulsionsor implants. Ampoules are convenient unit dosages.

For enteral application, particularly suitable are tablets or drageeswhich are also characterized by talc and/or a carbohydrate carrier orbinder or the like, the

carbohydrate carrier being preferably lactose and/or corn starch and/orpotato starch. A syrup or the like can also be used wherein a sweetenedvehicle is employed.

For topical application, viscous to semi-solid forms are used such asliniments, salves or creams, which are, if desired, sterilized, or mixedwith auxiliary agents, such as preservatives, stabilizers, or wettingagents, or salts for influencing the osmotic pressure, or with buffersubstances.

The substances of this invention are generally administered to animals,including, but not limited to, mammals and avians, e.g., cattle, cats,dogs, and poultry. A daily dosage comprises about 0.1-2.0 g. activecompound of this invention" and l-5,000 mg. of pharmaceuticallyacceptable carrier. The dose can be given all at once or as divideddosages throughout the day. In general, the mg/kg ratio is preferablyabout l to 20 mg per kg of body weight.

Whereas, it is preferred to administer the compounds orally, vaginaltablets and suppositories are also quite useful, particularly fortreatment against Trichomonas vaginalis.

The previously referred to tables now follow:

TABLE I Compound Minimum Inhibitory Concentration in -y/ml againstTrichomonas vaginalis Comparative substance V] l 00 2-(S-nitro-Z-furfurylL dene )-5-methoxyl -indanone 0.05 2-( 5 -nitro-2-furfurylidene)-4-methoxy l-indanone 05 2 5 -nitro-2-furfurylidene)-5-hydroxyl -indanone 0.05 2-( 5-nitro-2-l'urfurylidene )-4-hydroxyl-indanone 0.05 2-(5-nitro-2-furfurylidene)-6-hydroxy-5-methoxyl-indanone 0.025

TABLE 11 (Minimum Inhibitory Concentrations in y/ml in the Plate Test)Mycobacterium Compound 2-(5-nitro- 2-(5-nitro- VI Z-furfuryl-2--furfurylidene)-6- idene(5-acetoxyhydroxy-S- l-indanonemethoxy-lindanone MJuberculnris 100 1 1 M.ba11ey 100 1 10 M.av1'um 50 5010 M.kansa.rii 50 50 10 TABLE lll (Minimum lnhibitory Concentrations in-y/ml) Microorganism Z-(S-nitt'o-Z-fur- 2-(5- nitro-2fl. 1r-2-(5-nitro-2- A: 2-(5-nitro 2-furturylidene)-4-methyl-l-indanone.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, utilize the present invention toits fullest extent. The following preferred specific embodiments are,therefore, to be construed as merely illustrative, and not limitative ofthe remainder of the specification and claims in any way whatsoever.

EXAMPLE 1 2-(5nitr0-2-furfurylidene)-5-methoxy-indanone a. 11.35 g. (70millimols) of S-methoxy-indanone is suspended in 140 ml. oforthophosphoric acid (85 percent), and 9.87 g. (70 millimols) ofnitrofurfural is added. The mixture is stirred for 6 hours at 50 C.,allowed to stand overnight at room temperature, and poured into icewater. The insoluble product is filtered off and recrystallized fromethanol.

Yield: 8.0 g. (40 percent of theory), m.p. 204C.

C H N Calculated 63.20 3.88 4.92 Found 63.45 3.82 4.92

b. 2.4 g. (10 millimols) of nitrofurfural diacetate is dissolved in 5ml. of glacial acetic acid and 0.35 ml. of concentrated H 80 thereaction solution is heated on a steam bath for 5 minutes, then cooledto C., and 1.62 g. 10 millimols) of -methoxy-indanone is added.

The mixture is agitated for 4 hours at room temperature, poured in icewater, and the precipitated product is filtered off and recrystallizedfrom nitromethane.

Yield: 1.6 g. (56 percent oftheory), m.p. 204 C.

c. 4.86 g. (20 millimols) of nitrofurfural diacetate and 3.2 g. (20millimols) of S-methoxy-indanone are stirred in 20 ml. oforthophosphoric acid (85 percent) for 5 hours at C.; then, the mixtureis poured into ice water, the thus-precipitated product is filtered offand recrystallized from glacial acetic acid.

Yield: 3.8 g. (67% of theory), m.p. 204 C.

EXAMPLE 2 2-(5-nitro-2-furfurylidene)-4-chloroindanone 1.66 g. (10millimols) of 4-chloroindanone is suspended in 20 ml. of orthophosphoricacid percent), and 1.41 g. (10 millimols) of nitrofurfural is added. Themixture is stirred for 6 hours at 50 C. and then poured into ice water;the insoluble product is fil tered off and recrystallized from dioxane.

Yield: 2.65 g. (92 percent of theory), m.p. 206 C.

C H CINQ, (289.7)

C H N c1 Calculated 58.00 2.78 4.84 12.25 Found 58.22 2.94 4.73 12.21

EXAMPLE 3 2-( 5-nitro-2-furfurylidene )-5-chloroindanone The process forthe preparation of this compound is conducted analogously to that setforth in Example 2, but using 1.66 g. of 5-chloroindanone.

Yield: 1.7 g. (59 percent of theory), m.p. 230-231 C. (from dioxane).

C H N Cl Calculated 58.00 2.78 4.84 12.25 Found 58.43 2.77 4.33 11.99

EXAMPLE 4 2-(5-nitro-2-furfurylidene)-6-chloroindanone The process forthe preparation of this compound is conducted analogously to that setforth in Example 2, but using 1.66 g. of 6-chloroindanone.

Yield: 1.75 g. (61 percent of theory), m.p. 206 C. (from dioxane).

C I-I CINQ, (289.7)

C. L l N Calculated 58.00 2.78 4.84 Found 57.92 3.33 4.63

EXAMPLE 5 2-(5-nitro-2-furfurylidene)-4-methyl-indanone The process forthe preparation of this compound is conducted as set out in Example 2,in an analogous manner, but employing 1.46 g. (10 millimols) of 4-methyl-indanone. l

Yield1 500 mg. (18 percent of theory), m.p. 20l-20 2 C. (from ethanol).

C, H, NO (270.3)

C H N Calculated 66.60 4.44 5.18 Found 6702 3.97 5.16

EXAMPLE 6 2-(5-nitro-2-furfurylidene)-6-methyl-indanone This compound isprepared analogously to Example 2, but employing 1.46 g. (10 millimols)of 6-methyl-indanone.

Yield: 2.3 g. (85 percent of theory), m.p. l73--175 C. (from dioxane).

EXAMPLE 7 2-(S-nitro-Z-furturylidene)-6-isopropyl-indanone This compoundis produced analogously to Example 2, but with 1.74 g. of6-lsopropyl-indanone.

Yield: 2.52 g. (87 percent oftheory), m.p. 151 C.

EXAMPLE 8 2-( 5 -nitro-2 -furfurylidene )-5 -hydroxy-indanone 2.96 g.(20 millimols) of S-hydroxy-indanone is suspended in 20 ml. oforthophosphoric acid (85 percent), and 2.82 g. (20 millimols) ofnitrofurfural is added. The reaction mixture is agitated for 7 hours at50 C., then poured in ice water, and the insoluble product is filteredoff and recrystallized from ethanol.

Yield: 0.95 g. (18 percent of theory), m.p. 230 C. (decomposition).

EXAMPLE 9 2-(5-nitro-2-furfurylidene )-7-methoxy-indanone Eight hundredmg. (5 millimols) of 7-methoxy-indanone and 700 mg. (5 millimols) of5-nitrofurfural are agitated in 10 m1. of orthophosphoric acid (85percent) for 6 hours at 50 C., poured in ice water, and the insolubleproduct is recrystallized from dioxane.

Yield: 1.1 g. (82 percent of theory), m.p. 242243 EXAMPLE 10 2-( 5-nitro-2-fu rfu rylidene )-5 -ethoxy-indanone 1.76 g. (10 millimols) of5-ethoxy-indanone and 1.41 g. l millimols) of S-nitrofurfural areagitated in 20 ml. of orthophosphoric acid (85%) for 6 hours at 50 C.,allowed to stand overnight, and poured in ice water. The insolubleproduct is recrystallized from ethanol.

Yield: 0.5 g. (17 percent of theory), m.p. 207-208 C. (decomposition).

C H N Calculated 64.30 4.38 4.68 Found 64.07 4.07 4.61

EXAMPLE 11 2-(5-nitro-2-furfurylidene)-5-methanesulfonyloxyindanone 2.26g. millimols) of Smethanesulfonyloxy-indanone and 1.4 g. (10 millimols)of S-nitrofurfural are stirred in 20 ml. of orthophosphoric acid (85percent) for 5 hours at 50 C. and allowed to stand overnight at roomtemperature. The insoluble product, precipitated with ice water, isrecrystallized from dioxane.

Yield: 1.8 g. (51 percent of theory), m.p. 225 C. (decomposition).

EXAMPLE 12 2-( 5-nitro-2-iurfurylidene )-benzofuranone-( 3) 1.34 g. (10millimols) of benzofuranone-(3) is suspended in 20 ml. of H PO, andmixed with 1.4 g. (10 millimols) of S-nitrofurfural. The mixture isstirred for 5 hours at 50 C., allowed to stand overnight at roomtemperature, and then poured in ice water. The insoluble product isfiltered off and recrystallized from ethanol.

Yield: 0.8 g. (32 percent of theory), m.p. 163-166 C.

EXAMPLE l3 2-( 5-nitro-2-furfurylidene )-thioindoxyl 1.5 g. (10millimols) of thioindoxyl is suspended in 25 ml. of orthophosphoric acid(85 percent), and 1.41 g. (10 millimols) of nitrofurfural is added. Athick crystalline sludge is produced at once, which is stirred with icewater after having been allowed to stand overnight. The insolubleproduct is filtered off and recrystallized from ethyl acetate.

Yield: 1.8 g. (66 percent of theory). m.p. 202-203 C ll- N0 8 (273.3)

. C H N S Calculated 57.20 2.58 5.12 l 1.70 Found 57.57 2.98 5.11 11.86

EXAMPLE 14 C H NO S (289.3)

C H N S Calculated 53.80 2.44 4.83 1 1.00 Found 53.49 2.19 4.92 10.83

EXAMPLE l5 3-(S-nitro-Z-t'urfurylidene)-chromanone 1.48 g. 10 millimols)of chromanone is suspended in 20 ml. of orthophosphoric acid (85percent), and 1.41 g. l0 millimols) of S-nitrofurfural is added. Themixture is stirred for 5 hours at 50 C., then allowed to stand overnightat room temperature, poured in ice water, and the insoluble product isrecrystallized from ethanol.

Yield: 0.9 g. (33 percent of theory), m.p. 180-182 C. (decomposition).

C H N Calculated 62.20 3.34 5.16 Found 61.66 3.56 4.93

EXAMPLE 16 3-( 5-nitro-2-furfurylidene )-7 -methoxyisothiachromanone3.88 g. (20 millimols) of 7-methoxyisothiachromanone and 2.82 g. (20millimols) of nitrofurfural are agitated in 20 ml. of orthophosphoricacid (85 percent) for 40 hours at room temperature; the recrystallizedproduct is vacuum filtered and recrystallized from ethyl acetate.

Yield: 3.9 g. (62 percent of theory). m.p. l90-192 C.

C H NO S (317.3)

c H N s Calculated 56.80 3.48 4.42 10.10 Found 56.49 3.44 4.26 10.1 1

EXAMPLE l7 C H NO S (333.3)

c H N s Calculated 54.10 3.32 4.21 9.62 Found 54.11 3.51 4.16 9.84

EXAMPLE 18 3-(5-nitro-2-furfurylidene)-thiachromanone 16.4 g. (0.1 mol)of thiachromanone is suspended in 75 ml. of orthophosphoric acid (85percent), and 14.1 g. (0.1 mol) of S-nitrofurfural is added; thereaction mixture is agitated for 5 hours at room temperature and allowedto stand for 2 days. Then, the mixture is poured in ice water, and theinsoluble product is recrystallized from dioxane.

Yield: 12.2 g. (42 percent of theory), m.p. 179 C. (decomposition).

C H NO S (287.3)

C H N S Calculated 58.60 3.16 4.88 11.18 Found 58.31 3.18 4.60 10.99

EXAMPLE 19 3-(5-nitro-2-furfurylidene)-thiachromanone-S-oxide 14.0 g.(48.7 millimols) of 3-(5-nitro-2-furfurylidene)-thiachromanone issuspended in 1.2 l. ofglacial acetic acid, and ml. of 30% H O, in 200ml. glacial acetic acid is added. After 3 hours of agitation, 10 ml. of30% H 0 is again added, and then the reaction mixture is stirred foranother 2 days. The substance is precipitated with ice water, and theinsoluble product is recrystallized from dioxane.

Yield: 11.3 g. (77 percent oftheory), m.p. l91-192 C H NO S (303.3)

C H N 8 Calculated 55.50 2.99 4.62 10.55 Found 55.70 2.80 4.28 10.36

EXAMPLE 20 3-(5-nitro-2-furfurylidene)-thiachromanone-S-dioxide 4.1 g.of thiachromanone-S-dioxide is suspended in 50 ml. of orthophosphoricacid percent), and 2.8 g. of S-nitrofurfural is added. The reactionmixture is stirred for 6 hours at room temperature and allowed to standfor 5 days. The mixture is precipitated with ice water, and theinsoluble product is leached by boiling with ethanol. The product, whichis insoluble in ethanol, is recrystallized from dioxane.

Yield: 1.2 g. (18 percent of theory), m.p. 2l4-2l7 C. (decomposition).

C H NO S (319.3)

C H N S Calculated 52.65 2.84 4.40 10.05 Found 52.97 3.12 4.15 9.86

EXAMPLE 21 2-(5-nitro-2-t1'1enylidene)-5-methoxy-indanone 1.62 g. (10millimols) of methoxy-indanone is suspended in 20 ml. of orthophosphoricacid (85 percent), and 1.57 g. l0 millimols) of 5-nitrothiophene-2-carboxaldehyde is added. The reaction mixture is agitated for 6 hours at50 C., then poured in ice water, and the insoluble product isrecrystallized from dioxane.

Yield: 1.5 g. (50 percent of theory), m.p. 250-252 C.

C H N S Calculated 60.00 3.60 4.60 10.70 Found 59.66 3.78 4.51 10.60

EXAMPLE 22 3-(5-nitro-2-thenylidene)-thiachromanone-S-oxide 3.8 g. (20millimols) of thiachromanone-Soxide and 3.14 g. (20 millimols) of5-nitrothiophene-2-carboxaldehyde are agitated in 20 m1. oforthophosphoric acid (85 percent) and ml. of benzene for 5 days at roomtemperature; then, the reaction mixture is poured in ice water, theinsoluble product is filtered off and recrystallized from dioxane.

Yield: 1.1 g. (17 percent of theory), m.p. 227 C. (decomposition).

c..1i,,1-10.s 319.4

C H N S Calculated 52.70 2.83 4.39 20.10 Found 53.07 3.20 4.58 20.18

EXAMPLE 23 2-( 5-nitro-2-furfurylidene )-5-fluoro- 1 -indanone Thepreparation of this compound is conducted analogously to Example 1(c),but with the use of 850 mg. of 5-fluoro-l-indanone. The product isrecrystallized from ethyl acetate.

Yield: 1.1 g. (71 percent of theory), (decomposition).

C l-1 FNO (273.2)

m.p. 222 c.

Calculated Found EXAMPLE 24 EXAMPLE 292-(S-nitro-Z-furfurylidene)-6-f1uoro-1-indanone2-(5-nitro-2-furfurylidene)-4-methoxy- 1 -indanone The preparation ofthis compound is conducted This compound is prepared analogously toExample analogously to Example 1(c), but with 1.5 g. of 6- 5 1(c),butemploying 400 mg. of 4-methoxy-l-indanone. fluoro-l-indanone. Yield:450 mg. (64 percent of theory), m.p. 223 C.

Yield: 2.0 g. (73 percent of theory), m.p. 212 C. (f th la mg y (fromethyl acetate).

C H NO, (285.3)

C 1-l FNO (273.2) C H N C H N Calculated 63.20 3.88 4.92 Calculated61.50 2.95 5.13 Fvund 63.34 I 3.83 4.82 Found 61.37 2.80 4.99

EXAMPLE 30 EXAMPLE 25 I l5 2-(S-mtro-Z-furfuryhdene)-6-methoxy-l-mdanoney l' y The preparation of this compound is conducted The Preparation ofthis p f is conducied analogously to Example 2, but with 1.2 g. of-methox- 311310801191) Exampie K but with 8- of y-lindanone. The productis recrystallized from dioxmethyl-l-indanone. ane.

Yield= s- Percent of y) -p- Yield: 1.78 g. as percent of theory), m.p.245 c. (from ethyl acetate (decomposition).

n H A C, -,H NO,(285.3)

N C l l t d 5.18 r3311 ii n'ii 1Z3? EXAMPLE 26 EXAMPLE 31 5 2411 -"y l'1 'indanone Q 2-( 5 -nitro-2-furfurylidene )-5 -methoxy-3 -methyl- 1 Thepreparation of this compound is conducted indanone analogously toExample 1(c), but with 1.46 g. of 7- This compound is preparedanalogous), to the methyl- 1 -indanone.

tf th' E 11 'th2.1.f-' Yield: 1.7 g. (63 percent of theory), m.p. 219 C.process Se or m xampe (c) but M g 0 5 methoxy-B-methyl-l-indanone. Theproduct' is (from ethyl acetate) recrystallized from ethyl acetate.

CUHHNQ (2703) Yield: 1.5 g. (42 percent of theory), m.p. 181-182 C.(decomposition). N Calculated 5.18 C H NO 2993 Found 5.15 7 w m 5( C H NEXAMPLE 27 Calculated 64.20 4.37 4.68

n I I Found 63.84 4.47 4.632-(S-mtro-Z-furfurylrdene)-3-methyl-l-1ndanone This compound is preparedanalogously to Example EXAMPLE 32 1(c), butwith 9.0g.of3-methyl-l-indanone. 45 ff Yield: 11.0 g. (66 percent of theory), m.p.151 c. i f 'ylldelw) 1 m (from ethylacemtfl' The preparation of thiscompound is conducted 0 2703 analogously to Example 2, but employing1.92 g. of

H N 4,5-dimethoxy-1-indanone. The product is recrystal- C lized fromglacial acetic acid.

4. 4 gglggated 223g A Yield: 2.1 g. (67 percent of theory). m.p. 249 C.

(decomposition). EXAMPLE 282-(5-nitro-2-furfurylidene)-5-hydroxy-3-methyl-l- EXAMPLE indanone 2-(S-nitro-Z-furfurylidene )-5 ,6-d'imethoxyl -in- The process for thepreparation of this compound is danOne conducted analogously to that ofExample 1(c), but This compound is prepared analogously to Example using900 mg. of 5-hydroxy-3-methyl-l-indanone. The but with gof yan n Theproduct is recrystallized from ethyl acetate. product is recrystallizedfrom glacial acetic acid.

Yield: 180 mg. (11 percent of theory), m.p. 234-23 Yield: 0.9 g. (28percent of theory), m.p. 257 C. 5 C. (decomposition). (decomposition).

C,,,l-l NO,(285.3) C l-l, NQ,(3l5 .3)

N N Calculated 4.9 1 1 Calculated 4.44

Found 4.82 Found 4.35

13 EXAMPLE 34 2-(5-nitro-2-furfurylidene)-6-hydroxy-5-methoxy-1-indanone The preparation of this compound is carried out analogously toExample 1(c), but with 8.9 g. of 6- hydroxy-S-methoxy-l-indanone. Theproduct is recrystallized from ethyl acetate.

Yield: 10.1 g. (67 percent of theory). m.p. 247 C.

(decomposition). 10

C,,,l-l,,NO (301.3)

C H N Calculated 59.90 3.68 4.65 Found 60.29 3.89 4.34

EXAMPLE 35 2-( 5 -nitro-2-furfurylidene )-5 -hydroxy-6-methoxyl indanoneThe process for the preparation of this compound is conductedanalogously to Example 1(c), but employing 1.78 g. of5-hydroxy-6-methoxy-l-indanone. The product is recrystallized fromethanol/dioxane.

Yield: 2.0 g. (61 percent of theory), m.p. 254 C. (decomposition).

EXAMPLE 36 2-(5-nitro-2-furfurylidene)-5-n-butoxy-l-indanone Thiscompound is prepared analogously to Example 2, but with 2.04 g. ofS-n-butoxy-l-indanone.

Yield: 2.4 g. (73 percent of theory), m.p. 175-176 C. (from ethylacetate).

c n uo (327.3)

C H N Calculated 66.05 5.23 4.27 Found 65.71 5.41 4.43

EXAMPLE 37 40 2-( 5-nitro-2-furfurylidene )-5-acetoxy- 1 -indanone Sixhundred mg. of S-acetoxy-l-indanone and 450 mg. of nitrofurfural arerefluxed for 5 hours in 20 ml. of acetic anhydride, cooled to 0 C., thecrystallized product is vacuum filtered and recrystallized from ethylacetate.

Yield: 300 mg. (33 percent of theory), m.p. 195-20 2 C. (decomposition).

C H NO 313.3)

C H N Calculated 61.34 3.54 4.47 Found 61.30 3.80 4.38

EXAMPLE 3s 2-( 5-nitro-2-furfurylidene )-7-acetoxyl -indanone 1.48 g. of7-hydroxy-l-indanone and 1.4 g. of nitrofurfural are refluxed in 40 ml.of acetic anhydride for 5 hours, cooled to 0 C., and the crystallizedproduct is recrystallized from ethyl acetate.

Yield: 1.] g. (35 percent of theory), m.p. 196-198 C.

C H NO (3 13.3)

N Calculated 4.47 Found 4.45

EXAMPLE 39 2-( 5-nitro-2-furfurylidene )-7-hydroxyl -indanone 1.7 g. of2-(S-nitro-Z-furfurylidene)-7-acetoxy-l-indanone is refluxed for 2 hoursin 40 ml. of ethanol and 20 ml. of concentrated hydrochloric acid. Thethusproduced precipitate is recrystallized from ethyl acetate.

Yield: 1.1 g. (78 percent of theory), m.p. l91-194 C. (decomposition).

C H N Calculated 62.00 3.35 i 5.16 Found 62.06 3.46 5.16

EXAMPLE 40 C H NO (327.3)

C H N Calculated 62.39 4.00 4.28 Found 62.43 4.12 3.96

EXAMPLE 41 2-(5-nitro-2-furfurylidene)-6-methoxy-3-benzofuranone 1.05 g.of 6-methoxy-3-benzofuranone and 0.91 g. of S-nitrofurfural are refluxedfor 5 hours in 10 ml. of acetic anhydride, then cooled to C.; thecrystallized product is vacuum filtered and recrystallized from dimethylformamide.

Yield: 1.2 g. (67 percent of theory), m.p. 232-235 C.

N Calculated 4.88 Found 4.99

EXAM PLE 42 2-(5-nitro-2-furfurylidene)-6-hydroxy-3-benzofuranone Thepreparation of this compound is conducted analogously to Example 1(c),but with 1.5 g. of 6- hydroxy-3-benzofuranone.

Yield: 505 mg. (18 percent of theory), m.p. 259-26 5 C. (from dimethylformamide).

C H-,NO (273.2)

N Calculated 5.13 Found 5.35

EXAMPLE 43 2-(5-nitro-2-furfurylidene )-6,7-dihydroxy-3- benzofuranoneThis compound is prepared analogously to Example 1(c), but employing1.66 g. of 6,7-dihydroxy-3- benzofuranone. The product is recrystallizedfrom dimethyl formamide.

Yield: 2.0 g. (69 percent of theory), m.p. 262265 C. (decomposition).

C,,H,N0, (289.2)

c H N Calculated 53.99 2.44 4.84 Found 54.30 2.30 4.110

EXAMPLE 44 2-(S-nitro-Z-furfurylidene )-6-acetoxy-3-benzofuranone 1.92g. of 6-acetoxy-3-benzofuranone and 1.4 g. of nitrofurfural are refluxedfor 5 hours in 40 ml. of acetic anhydride. The crystallized productobtained by cooling to 70 C. is recrystallized from ethyl acetate.

Yield: 0.9 g. (29 percent of theory), m.p. l72-173 C. (decomposition).

N Calculated 4.44 Found 4.33

EXAMPLE 45 2-(5-nitro-2-furfurylidene)-6,7-cliacetoxy-3- benzofuranone1.66 g. of 6,7-dihydroxy-3-benzofuranone and 1.4 g. of S-nitrofurfuralare refluxed for 5 hours in 20 ml. of acetic anhydride, then cooled to70 C.; the crystallized product is vacuum filtered and recrystallizedfrom ethyl acetate. v

Yield: 1.7 g. (46 percent of theory), m.p. 209210 C. (decomposition).

c H N Calculated 54.70 2.97 3.75 Found 54.58 2.93 3.57

EXAMPLE 46 3-( 5-nitro-2-t'urfury1idene )-7-acetoxy-chromanone 1.64 g.of 7-hydroxy-chromanone and 1.40 g. of 5- nitrofurfural are refluxed in20 ml. of acetic anhydride for 5 hours, cooled to -70 C., and thethus-obtained crystallized product is recrystallized from ethyl acetate.

Yield: 1.2 g. (36 percent of theory), m.p. l76-l78 C. (decomposition).

. C H N Calculated 58.36 3.37 4.25 Found 58.16 3.39 4.1)4

EXAMPLE 47 3-(5-nitro-2-furfurylidene )-7-methoxythiachromanone 3.88 g.of 7-methoxy-thiachromanone and 2.82 g. of S-nitrofurfural are refluxedfor 3.5 hours in 60 ml. of acetic anhydride; the substance whichcrystallizes after allowing the reaction mixture to stand for 24 hoursis recrystallized from acetone.

Yield: 0.55 g. (9 percent of theory), m.p. 173 C. (decomposition).

C H NO S (317.3)

8 Calculated 10.57 Found 10.41

EXAMPLE 48 2-( S-nitro-Z-thenylidene )-5-hydroxyl -indanone Thepreparation of this compound is conducted analogously to Example 1(c),but with 1.48 g. of 5- hydroxy-l-indanone and 2.6 g. of5-nit1'othiophene'2- carboxaldehyde. The product is recrystallized fromethyl acetate.

Yield: 1.5 g. (53% of theory), m.p. 2355-238" C. (decomposition).

S Calculated l 1 l 6 Found 1 1.30

EXAMPLE 49 C,,,H,,NO .,S (317.3)

c H N s Calculated 56.80 3.49 4.42 10.09. Found 56.47 3.51 4.51 9.83

EXAMPLE 50 3-(5-nitr0-2-thenylidene)-chromanone This compound isprepared analogously to Example 2, but with 1.48 g. of chromanone and1.57 g. of 5- nitrothiophene-2-carboxaldehyde. The product isrecrystallized from ethyl acetate.

Yield: 0.9 g. (32 percent of theory), m.p. 198202 C. (decomposition).

C H NO S (287.3)

c H N 5 Calculated 58.55 3.16 4.88 11.14 Found 58.50 3.32 4.78 11.20

1 EXAMPLE 51' 2-(5-nitro-2-furfurylidene)-3-phenyl-l-indanone Thepreparation of this compound is conducted analogously to Example 1(c),but with 4.16 g. of 3- phenyld -indanone.

Yield: 2.7 g. (41 percent of theory), m.p. 248 C. (from ethyl acetate).

C H NO, (331 .4)

N Calculated 4.24 Found 4.14

EXAMPLE 52 2-( 5-ni tro-2-furfurylidene )-5-benzyloxy- 1 -indanone 4.3g. of S-benzyloxy-l-indanone and 2.54 g. of nitrofurfural are refluxedin 30 ml. of acetic anhydride for 5 hours. The solution is then cooledto 70 C.; the product which crystallizes is vacuum filtered andrecrystallized from ethyl acetate.

Yield: 1.15 g. 18 percent oftheol'y), m.p. 224-225 C. (decomposition).

C H N Calculated 69.79 4.18 3.88 Found 69.72 4.49 3.86

EXAM PLE 5 3 2-(5-nitro-2furfurylidene)-5-ethoxyethoxy-1-indanone Thepreparation of this compound is conducted analogously to Example 1(c),but with 2.2 g. of 5- ethoxy-ethoxy- 1 -indanone.

Yield: 2.4 g. (70 percent of theory). m.p. l45-l47 C. (from ethylacetate).

C H N Calculated 62.98 4.99 4.08 Found 62.98 4.99 4.18

EXAMPLE 54 2-(5-nitropyrrol-2-y(-methylene)-l-indanone 1.3 g. l-indanoneand 1.4 g 5-nitropyrrole-2-carboxyaldehyde are stirred in ml.orthophosphoric acid for 5 hours at 60 C. The reaction mixture is thenpoured into ice-water, and the resultant insoluble product isrecrystallized from dioxane.

Yield: 0.80 g (31 percent of theory); m.p. 260 C.

Calculated 66.0 3.95 l 1.00 Found 66.40 4.23 10.97

EXAMPLE 55 4-methyl-2-(nitropyrrol-2-yl-methylene )-l-indanone Thesynthesis is conducted according to Example 54, however, with 444 mg.4-methyl-l-indanone.

Yield: 750 mg. (92 percent of theory); m.p. above 280 C. (fromdimethylformamide).

C, H, N,O (268.3)

Calculated N 10.43 Found N 10.62

EXAMPLE 56 5-methoxy-2-(5-nitropyrrol-2-yl-methylene)-l-indanone 1.16 gof 5-methoxy-1-indanone and 1.0 g of S-nitro- Z-pyrrol-aldehyde arestirred in 20 ml of orthophosphoric acid at 60 C for 1 hour and then at80 C for 5 hours. The mixture is poured into ice-water. The insolubleproduct is filtered olT and recrystallized from ethanol.

Yield: 1.7 g (84 percent of theory); m.p. 240 C.

C H N Calculated 63.3 4.25 9.86 Found 63.31 4.70 9.78

EXAMPLE 5';

200.0 g. of 2-(5-nitro-2-furfurylideneJ-S-methoxy-1- indanone, 105.34 g.of corn starch, 8.0 g. of gelatin, white, 6.5 g. of talc, 0.112 g. ofmethyl-p-hydroxybenzoate and 0.048 g. of propyl-p-hydroxybenzoate arehomogeneously mixed together and compressed to tablets of 320 mg. eachon a tabletting press in a conventional manner.

EXAMPLE 58 2.0 g. of 2-(5-nitro-2-furfurylidene)-6-hydroxy-5-methoxy-l-indanone, 27.0 g. of lactose, 45.565 g. of 4 corn starch, 4.0g. of talc, 1.4 g. of gelatin, white, 0.024 g. ofmethyl-p-hydroxybenzoate and 0.01 l g. of propylp-hydroxybenzoate arehomogeneously mixed and compressed to tablets of 80 mg. each on atabletting press in a conventional manner.

EXAMPLE 59 10.0 g. of 2-(5-nitro-2-furfurylidene)-6-hydroxy-5-methoxy-l-indanone, 60.0 g. of lactose, 4.9 g. of corn starch, 800 mg ofmagnesium stearate, 8 mg. of the methyl ester of p-hydroxybenzoic acidand 3.5 mg of the propyl ester of p-hydroxybenzoic acid arehomogeneously mixed and compressed into vaginal tablets of about 750 mgin a conventional manner.

EXAMPLE 6O C 11 N Cl Calculated 51.23 2.87 3.98 10.08 Found 51.43 3.144.17 10.12

EXAMPLE 61 5-cl1loro 4.6dimethyl-2-(.5-nitro-2-furfurylidene)-3-benzofuranone 0.62 g of 5-chloro-4.6-dimethy1-3-benzofuranone and 0.56 gof 5-nitrofurfural are refluxed in 4 m1. of acetic anhydride for 5hours. The solution is then cooled to C and the resultant insolubleproduct is recrystallized from dimethyl formamide.

Yield: 0.1 g (7.8 of theory); m.p. 259-262 C. (decomposition).

c H N c1 Calculated 56.35 3.15 4.33 1 1.09 Found 56.38 3.40 4.40 10.79

EXAMPLE 62 3.4-dimethyl-7-acetoxy-2-(5-nitro-2-furfurylidene)-l-indanone 1.4 g of 3.4-dimethyl-7-hydroxy-1-indanone and 1.13 g of5-nitrofurfural are refluxed in 8 ml. acetic anhydride for 5 hours. Thesolution is then cooled to 70 C and the obtained crystallized product isrecrystallized from ethanol.

Yield: 0.9 g 33 percent of theory); m.p. l73176 C. (decomposition).

c H N Calculated 66.42 4.05 4.70 Found 66.42 4.83 4.46

EXAMPLE 64 6-butury1oxy-2-(S-nitro-Z-furfurylidene)-3-benzofuranone 1.09g (4 millimoles) of6-hydroxy-2-(S-nitro-Z-furfurylidene-)-3-3-benzofuranone were heated in20 m1. of butyric acid anhydride for 80 minutes at 140 C. The mixturewas diluted with petroleum ether and the precipitate was filtered offand recrystallized from ethyl acetate.

Yield: 0.5 g (38 percent of theory); m.p. 106-170 C H N Calculated 59.483.82 4.08 Found 59.49 3.61 4.06

The preceding examples can be repeated with similar success bysubstituting the generically or specifically described reactants and/oroperating conditions of this invention for those used in the precedingexamples.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Consequently, such changes and modifications are properly,equitably, and intended to be, within the full range of equivalence ofthe following claims.

What is claimed is:

l. A compound of the formula:

l l I OzN OH- wherein Xis 0; Y is O; -O-CH,; or CA A being H, methyl,

or ethyl; and

R,, R, and R each represent alkyl, hydroxy, alkoxy,

c lox ,alk lsulfon 10x rou 5 herein each 1- iyl al oxy r acyl residiieis n t ore than 5 e rbon atoms and acyl is derived from an alkanecarboxylic acid; or hydrogen, with the provision that at least one ofR,, R R is said hydroxy or acyloxy.

2. A compound as defined by claim 1 wherein Y is CH,, at least two of R-Rg, are other than hydrogen, and at least one is said alkoxy orhydroxy.

3. A compound as defined by claim 1 wherein one of Fi -R is hydroxy andanother of R,-R is said alkoxy.

4. A compound as defined by claim 1 wherein Y is CH,--, and at least oneof R R is hydroxy.

5. A compound as defined by claim 1 wherein at least one of R -R, is H.

6. A compound as defined by claim 1 wherein Y is CH 7. A compound asdefined by claim 1 wherein said compound is selected from the groupconsisting of2-( 5- nitroQ-furfurylidene)-5-acetoxy-l-indanone; and2-(5- nitro-Z-furfurylidene)-7-acetoxy- 1 -indanone.

8. A compound as defined by claim 1 wherein said compound is selectedfrom the group consisting of 2-(5-nitro-2-furfurylidene)-7-hydroxy-l-indanone; 2-(5-nitro-Z-furfurylidene)-5-propionyloxy-l-indanone; and4-methyl-2-(nitropyrrol-Z-yl-methylene)- l -indanone.

9. A compound as defined by claim 1 wherein said compound is selectedfrom the group consisting of 3.4-dimethyl-7-acetoxy-2-(S-nitro-2-furfurylidene)-1-indanone; and3.4-dimethyl-7-hydroxy-2-(5-nitro-2-furfury1idene)- 1 -indanone.

10. A compound as defined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5-hydroxy-1- indanone.

l l. A compound as defined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-S-acetoxy-lindanone.

12. A compound as defined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5- propionyloxy- 1 -indanone.

13. A compound as defined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5,6-dihydroxyl -indanone.

1. A compound of the formula:
 2. A compound as defined by claim 1wherein Y is -CH2-, at least two of R1-R3 are other than hydrogen, andat least one is said alkoxy or hydroxy.
 3. A compound as defined byclaim 1 wherein one of R1-R3 is hydroxy and another of R1-R3 is saidalkoxy.
 4. A compound as defined by claim 1 wherein Y is -CH2-, and atleast one of R1-R3 is hydroxy.
 5. A compound as defined by claim 1wherein at least one of R1-R3 is H.
 6. A compound as defined by claim 1wherein Y is -CH2-.
 7. A compound as defined by claim 1 wherein saidcompound is selected from the group consistingof2-(5-nitro-2-furfurylidene)-5-acetoxy-1-indanone; and2-(5-nitro-2-furfurylidene)-7-acetoxy-1-indanone.
 8. A compound asdefined by claim 1 wherein said compound is selected from the groupconsisting of 2-(5-nitro-2-furfurylidene)-7-hydroxy-1-indanone;2-(5-nitro-2-furfurylidene)-5-propionyloxy-1-indanone; and4-methyl-2-(nitropyrrol-2-yl-methylene)-1-indanone.
 9. A compound asdefined by claim 1 wherein said compound is selected from the groupconsisting of3.4-dimethyl-7-acetoxy-2-(5-nitro-2-furfurylidene)-1-indanone; and3.4-dimethyl-7-hydroxy-2-(5-nitro-2-furfurylidene)-1-indanone.
 10. Acompound as defined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5-hydroxy-1-indanone.
 11. A compound asdefined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5-acetoxy-1-indanone.
 12. A compound asdefined by claim 1, wherein said compound is2-(5-nitro-2-furfurylidene)-5-propionyloxy-1-indanone.